The field of the invention is activating protein synthesis to promote regeneration of a lesioned CNS axon and compensatory regrowth of a spared axon in the mature CNS.
Axon regeneration failure following injury in the adult mammalian CNS has been attributed mainly to two properties of the adult CNS, namely the inhibitory extrinsic environment and diminished intrinsic regenerative capacity of mature CNS neurons (1-5). Numerous studies on the non-permissive environment have led to the identification of a number of molecular players and signaling pathways involved in limiting axon regrowth. While these mechanisms clearly represent important extrinsic barriers for axon regeneration, the strategies to neutralize these inhibitory activities only allowed a limited degree of axon regeneration in vivo (6, 7). Indeed, a permissive environment, such as a sciatic nerve graft transplanted to the lesion site, allows a small percentage of injured adult axons to regenerate (5, 8). These results indicate that neutralizing inhibitory activity is not sufficient and therefore other mechanisms, such as those controlling the intrinsic axonal regenerative potential of neurons, may play an important role in axon regeneration.
In contrast to the axon growth during embryonic development, little is known about the molecular mechanisms that control the intrinsic regenerative ability of adult CNS neurons (1, 3-5, 9). It is also unknown whether similar or different mechanisms operate axon growth during development and axon regeneration following injury and what accounts for the decreased ability of axon growth over the course of development. Both transient and sustained axon sprouting has been documented in the adult CNS as the anatomical basis of structural plasticity in response to activity deprivation (10). The reason for this reorganization of axons as a compensatory mechanism, in the face of failure to regenerate injured axons, is also unclear. A potential hint to these questions comes from the evolutionarily conserved molecular pathways that control cellular growth and size. It is believed that for most of cell types, specific mechanisms are necessary in preventing cellular overgrowth upon the completion of development (11). Since many of these molecules are often expressed in post-mitotic mature neurons, we hypothesized that these pathways may contribute to the diminished regenerative ability in adult CNS neurons.
By testing different pathways involved in cell growth control in an optic nerve injury model, we show that inhibiting PTEN (phosphatase and tensin homolog), a negative regulator of the mammalian target of rapamycin (mTOR) pathway, in the adult retinal ganglion cells (RGCs) promotes striking axon regeneration. Further studies revealed a two-step suppression of mTOR signaling in adult CNS neurons: first by developmental maturation and second by axotomy-triggered stress response. Such inhibition of mTOR activity and subsequent impairment in new protein synthesis ability contributes to their inability to regenerate injured axons. Reactivating this pathway by inhibiting tuberous sclerosis complex 1 (TSC1), another negative regulator of the mTOR pathway, also leads to extensive long-distance axon regeneration. Our work shows that general growth control pathways regulate axon regenerative abilities in neurons, thereby providing new strategies to promote axon regeneration after CNS injury such as spinal cord injury, stroke, traumatic brain injury and glaucoma.
Subsequent to our priority filing date, Nakashima et al. (J Neurosci (2008 Jul. 16) 28(29):7293-303) reported small-molecule protein tyrosine phosphatase inhibition using potassium bisperoxo(1,10-phenanthroline)oxovanadate (V) as a neuroprotective treatment after spinal cord injury in adult rats.